The long term objective is to carry out rational development of novel anti-AIDS drugs with high potency, low toxicity, and broad clinical applicability. We have discovered several new anti-HIV agents from distinct and unrelated plant species. Some of these are proteins, whereas others are organic polycyclic compounds. These agents exhibit dose-dependent inhibition of cell free HIV-1 infection and replications measured by: a) quantitative focal syncytium formation on CEM-ss monolayers, b) viral core protein p24 expression, and c) viral-associated reverse transcriptase activity in HIV infected H9 cells. We wish to study the structure-function relationship of these anti-HIV compounds so as to enable the rational design of safer and more effective analogues of anti-AIDS drugs. Peptide sequences and conformational requirements responsible for the anti-AIDS activities and cytotoxicity would be mapped. This may make possible the design of specific peptide fragments which may be useful as anti-HIV drugs with less immuno-genicity and improved pharmacokinetic properties (gut stability, biologic half-life, etc.) than their parent proteins. These sequences may then be further modified by targeted design to modulate and enhance their bioactive properties. We would also study the molecular mechanisms of the anti-HIV activity of these compounds so as to learn new strategies for the prevention and treatment of AIDS. A combination of biochemical, cellular, histochemical, and molecular methods will be used to conduct these studies. If the basis of the anti-HIV activity of these compounds lies in selective interactive or uptake, these may be of use in engineering the delivery of these and other drugs for patient treatment. If the basis of their action lies in a fundamental biochemical difference between HIV-infected cells and normal cells, this difference may be investigated and exploited in new interventions of AIDS.